Host immunity to cancers has been extensively documented both in animal models and humans (1). In fact, there is strong evidence that the immune surveillance plays a critical role in limiting tumor outgrowth in the early stages of tumorigenesis (2, 3). However, the ability to prime tumor-specific T-cells and sustain an immune response that imparts a measurable clinical benefit, is limited in the setting of an established tumor burden (4, 5). Taken together, these findings suggest numerous requirements for effective immunotherapy. Tumor-specific T cells must not only possess a sizeable precursor frequency and reach sufficient numbers following activation, but they must also be able to traffic to the tumor site and effectively kill their targets in situ.
Growing tumors are able to modify their microenvironment and render it more immunosuppressive. Such intratumoral changes include altering the cytokine milieu, changing the extracellular matrix, and recruiting immune cells with a suppressive function. In mice, the CD11b+/Gr1+ MSCs represent one population of cells within the tumor microenvironment responsible for the immunosuppression accompanying tumor growth (6, 7). Their elimination in tumor-bearing hosts restores CD8+ T cell responsiveness (8, 9). This observation points to a reversible process and supports the hypothesis that strategies aimed at the pharmacologic inhibition of these pathways can be effective in restoring immune responsiveness. L-Arginine metabolism is a key pathway used by MSCs to blunt the anti-tumor response both in mice and humans ((10, 11) and Serafini, Noonan unpublished data). Arg1 and NOS2, the main enzymes that catabolize L-arginine, can, in fact, work either alone or synergistically in restrain T-cells response (12). Through an understanding of these critical suppressive pathways, it is possible to determine whether selective immunopharmacologic targeting can augment anti-tumor immunity. Nitroaspirin derivatives were recently shown to down-regulate NOS2 expression in tumor associated MSCs and to abrogate MSC-mediated immune-suppression in vivo (13) but the mechanisms of these effects were not defined. While the transcriptional and posttranscriptional mechanisms regulating NOS2 expression have been extensively studied, little is known about the pathways regulating Arginase expression.
Agents increasing intracellular cGMP levels can induce either positive or negative effects on NOS2 in a cell dependent manner (14). In macrophages, for example, cGMP analogues inhibit NOS2 expression (15). Phosphodiesterase-5 (PDE5) inhibitors such as (sildenafil (Viagra®), vardenafil (Levitra®), tadalafil (Cialis®)) increase intracellular concentrations of cGMP with therapeutic implications that include the treatment of erectile dysfunction, (16) pulmonary hypertension (17) and cardiac hypertrophy (18). The results delineated herein relate to new mechanisms and functions involving PDE inhibitors, thus providing new therapeutic compositions and methods for treating or preventing disease and disease symptoms.